Schaeffer E M, Marchionni L, Huang Z, Simons B, Blackman A, Yu W, Parmigiani G, Berman D M
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Oncogene. 2008 Dec 4;27(57):7180-91. doi: 10.1038/onc.2008.327. Epub 2008 Sep 15.
Cancer cells differentiate along specific lineages that largely determine their clinical and biologic behavior. Distinct cancer phenotypes from different cells and organs likely result from unique gene expression repertoires established in the embryo and maintained after malignant transformation. We used comprehensive gene expression analysis to examine this concept in the prostate, an organ with a tractable developmental program and a high propensity for cancer. We focused on gene expression in the murine prostate rudiment at three time points during the first 48 h of exposure to androgen, which initiates proliferation and invasion of prostate epithelial buds into surrounding urogenital sinus mesenchyme. Here, we show that androgen exposure regulates genes previously implicated in prostate carcinogenesis comprising pathways for the phosphatase and tensin homolog (PTEN), fibroblast growth factor (FGF)/mitogen-activated protein kinase (MAPK), and Wnt signaling along with cellular programs regulating such 'hallmarks' of cancer as angiogenesis, apoptosis, migration and proliferation. We found statistically significant evidence for novel androgen-induced gene regulation events that establish and/or maintain prostate cell fate. These include modulation of gene expression through microRNAs, expression of specific transcription factors, and regulation of their predicted targets. By querying public gene expression databases from other tissues, we found that rather than generally characterizing androgen exposure or epithelial budding, the early prostate development program more closely resembles the program for human prostate cancer. Most importantly, early androgen-regulated genes and functional themes associated with prostate development were highly enriched in contrasts between increasingly lethal forms of prostate cancer, confirming a 'reactivation' of embryonic pathways for proliferation and invasion in prostate cancer progression. Among the genes with the most significant links to the development and cancer, we highlight coordinate induction of the transcription factor Sox9 and suppression of the proapoptotic phospholipid-binding protein Annexin A1 that link early prostate development to early prostate carcinogenesis. These results credential early prostate development as a reliable and valid model system for the investigation of genes and pathways that drive prostate cancer.
癌细胞沿着特定谱系分化，这在很大程度上决定了它们的临床和生物学行为。不同细胞和器官的独特癌症表型可能源于胚胎中建立并在恶性转化后得以维持的独特基因表达谱。我们利用全面的基因表达分析来研究前列腺中的这一概念，前列腺是一个具有易于研究的发育程序且癌症易感性高的器官。我们聚焦于在暴露于雄激素的头48小时内的三个时间点，小鼠前列腺原基中的基因表达，雄激素会引发前列腺上皮芽向周围泌尿生殖窦间充质的增殖和侵袭。在此，我们表明雄激素暴露调节先前与前列腺癌发生相关的基因，这些基因包括磷酸酶和张力蛋白同源物（PTEN）、成纤维细胞生长因子（FGF）/丝裂原活化蛋白激酶（MAPK）以及Wnt信号通路，以及调节癌症“特征”（如血管生成、凋亡、迁移和增殖）的细胞程序。我们发现了新的雄激素诱导的基因调控事件的统计学显著证据，这些事件建立和/或维持前列腺细胞命运。这些包括通过微小RNA调节基因表达、特定转录因子的表达以及对其预测靶点的调控。通过查询来自其他组织的公共基因表达数据库，我们发现早期前列腺发育程序并非普遍表征雄激素暴露或上皮芽形成，而是更类似于人类前列腺癌的程序。最重要的是，与前列腺发育相关的早期雄激素调节基因和功能主题在越来越致命的前列腺癌形式之间的对比中高度富集，证实了前列腺癌进展中胚胎增殖和侵袭途径的“重新激活”。在与发育和癌症联系最紧密的基因中，我们强调转录因子Sox9的协同诱导以及促凋亡磷脂结合蛋白膜联蛋白A1的抑制，它们将早期前列腺发育与早期前列腺癌发生联系起来。这些结果证明早期前列腺发育是用于研究驱动前列腺癌的基因和途径的可靠且有效的模型系统。
